We aim at understanding the role of the complosome in both initiation (IFN-gamma production) and contraction (IL-10 switching) of human Th1 responses as well as CD8+ CTL biology. A. We have now shown that the complosome and autocrine CD46 engagement is also required for normal IFN-g secretion and cytotoxic activity of human CD8+ T cell responses via regulation of fatty acid metabolism. B. Regulation of C3 and C5 gene expression: The controlled regulation of C3 and/or C5 gene expression - ideally from the cell surface - would be an additional means to manipulate Th1 and CTL responses at will. In collaboration with Steve Holland (NIAID, NIH), Mariana Kaplan (NIAMS) and Niki Moutsopolous (NIDCR), we have identified the integrin LFA-1 as a master regulator of C3 gene expression in a range of immune cells. Thus, patients with deficiency in LFA-1 (LAD-1 patients) have reduced C3 expression and defective Th1 responses - which can be rescued in vitro via provision of intracellular C3a. This work also identified the gene expression induction of a virtually complete complement system as the most significant and defining feature of tissue resident vs. circulating immune cells. We are currently actively defining the role of single complosome components in immune cell tissue residency. C. Direct regulation of IL-10 production in T cells: We have demonstrated that complosome-regulated intrinsic flux of cholesterol (and subsequent cMAF transcription factor activation) in human CD4+ T cells is required for successful IL-10 induction. We further published a computational model in which the complosome-driven expression and pairing of STAT proteins tips the balance between Th1 induction and contraction in human CD4+ T cells. D. Extension of work to natural regulatory T cells. In a project driven by Ben Afzali (NIDDK), we helped identifying a subset of natural CD161-positive regulatory T cells that have wound healing capacity. We are currently assessing the role of the complosome in nTreg activity.